Substituted piperidinoalkylthianaphthenes and benzofurans



United States Patent 3,476,760 SUBSTITUTED PIPERIDINOALKYLTHIA-NAPHTHENES AND BENZOFURANS Carl Kaiser, Haddon Heights, N .J., andCharles L. Zirkle,

Berwyn, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No Drawing.Continuation-impart of application Ser. No. 620,628, Mar. 6, 1967. Thisapplication Sept. 22, 1967, Ser. No. 669,707

Int. Cl. C07d 63/18, 29/34; A61k 27/00 US. Cl. 260-2934 18 ClaimsABSTRACT OF THE DISCLOSURE This application is a continuation-impart ofcopending application Ser. No. 620,628, filed Mar. 6, 1967, and nowabandoned.

This invention relates to thianaphthene and benzofuran compounds havingpharmacological activity. In particular, the invention relates to4-aryl-4-hydroxypiperidinoalkyl derivatives of thianaphthenes andbenzofurans having tranquilizing and analgesic activity.

The compounds of the invention are represented by the followingstructural formula:

wherein:

R is hydrogen, chloro, bromo, fluoro, trifluoromethyl, lower alkyl of upto about 4 carbon atoms, or lower alkoxy of up to about 4 carbon atoms;

ip m Y Y (:0 0H

III IV 3,476,760 Patented Nov. 4, 1969 R is hydrogen, chloro, bromo,methyl, trifluoromethyl, fluoro, or methoxy;

R is hydrogen or methyl;

R is hydrogen or lower alkanoyl of up to 6 carbon atoms; I

Y is sulfur, sulfone, or oxygen; and

n is a positive integer from 2 to 4.

Also part of the invention are the pharmaceutically acceptable acidaddition salts of the compounds of Formula I. Among these salts are thehydrochloride, hydrobromide, sulfate, nitrate, maleate, tartrate,citrate, or ethanedisulfonate.

Among the preferred groups of compounds are those where R is hydrogen,chloro, and fluoro and is at the 5 or 6-position; R is hydrogen, chloro,or fluoro and is at the p-position; R is hydrogen; R is hydrogen; Y issulfur; and n is 3.

A further group of compounds considered part of the present inventionare the intermediate compounds represented by the following structuralformula:

where R, R R, n, and Y are as defined above.

Another group of compounds considered part of the invention are those ofthe following structural formula,

vhich are active as tranquilizers:

R R2 R1 (Grim-N: Y

IIb

where R, R R n, and Y are as defined above.

The compounds of the invention are prepared by various methods which arehereinbelow described. They involve condensation of a4-phenyl-4-piperidinol with a derivative of an optionally substitutedbenzofuranor thianaphthenealkanoic acid. Such derivatives may be anester anhydride with ethyl chloroformate, an acid halide, or a diazoketone.

The compounds of the invention where n is 3 and R is hydrogen arepreferably prepared according to the procedures illustratedschematically below:

i R1 LCHZCWN Q OH Y II VI A 2 or 3-halomethylthianaphthene or benzofuran(III) is condensed with diethyl malonate in the presence of a base suchas sodium ethoxide or sodium hydride to give a substituted malonicester, which is then hydrolyzed with aqueous alkali to give the malonicacid IV. Decarboxylation by heating at about ZOO-250 results in theformation of a substituted propionic acid (V), which is then condensedwith ethyl chloroformate to give an ester anhydride (VI). Reaction witha 4-phenyl-4-piperidinol results in the formation of an intermediateamide (Ila). Reduction of this amide with a reagent such as lithiumaluminum hydride in ether or tetrahydrofuran gives the final product Ia.The final product is converted to an acid addition salt by bringingtogether the free base, which may be dissolved in a solvent such asether, alcohol, or acetone with the acid, which also may be in solution.A preferred method of salt formation involves the addition of etherealhydrogenchloride to an ether solution of the free base.

The starting materials are either described in the literature or areprepared from known materials by means of published methods. Forexample, thianaphthene-3-propionic acid is described in Bull. Soc. Chim.France 1953, 18590; 2-chloromethylthianaphthene is described in I. Am.Chem. Soc. 71, 2857 (1949); 2-chloromethylbenzofuran is described in J.Am. Chem. Soc. 73, 4400 (1951); 3-chloromethylthianaphthene is describedin J. Chem. Soc. 1961, 1291-7; general methods for preparing substituted2 or 3-halomethylthianaphthenes and benzofurans are described in U.S.Patent 3,070,606,

The 3-halomethylthianaphthene starting materials are convenientlyprepared from substituted thiophenols, as follows:

The substituted thiophenol is dissolved in an aqueous solutioncontaining an equivalent amount of an alkali metal hydroxide, such assodium or potassium hydroxide, and treated with an equivalent amount ofchloroacetone at about for 20 to 60 minutes. The reaction mixture isdiluted with a water-immiscible solvent such as ether. The organic layeris separated, solvent evaporated and the residue distilled in vacuo toobtain the l-phenylmercapto-Z-propanone. This propanone is cyclized byheating at 160180 for -45 minutes with a dehydrating agent, such as zincchloride or, preferably, phosphorus pentoxide, to obtain the3-methylthianaphthene, which is then treated with a halogenating agentsuch as, preferably, N-bromosuccinimide to give the3-bromomethylthianaphtheme.

The 2-halomethylthianaphthene starting materials are prepared asfollows:

An ether solution of the thianaphthene is added to an ether solutioncontaining lithium and butyl bromide, butyl lithium being present inabout a four-fold excess, and the mixture refluxed for one to two hours.Approximately a four-fold excess of gaseous formaldehyde is bubbled intothe solution over a period of three to five hours. Water and a loweralcohol, such as ethanol, are added; the mixture is made acidic withhydrochloric acid; the ether layer is separated and evaporated to obtainthe Z-hydroxymethylthianaphthene as the residue, which is purified byrecrystallization from a suitable solvent, such as n-heptane. Reactionof the hydroxymethyl compound with a chlorinating agent, such asphosphorus trichloride, phosphorus pentachloride or, preferably, thionylchloride, yields the starting material, Z-chloromethylthianaphthene.

A 3-halomethylbenzofuran starting material is conveniently prepared bybromination of a 3-methylbenzofuran with at least two molar equivalentsof N-bromosuccinimide in the presence of a catalytic amount of benzoylperoxide to give the 2-bromo-3-bromomethylbenzofuran which is thentreated as outlined previously, except that at some point during thereaction sequence, preferably after the decarboxylation, the2-bromo-3-propionic acid is hydrogenated in the presence of a catalystsuch as Raney nickel to remove the Z-bromine.

The 2-halomethylbenzofuran starting materials are prepared from acoumarilic acid by reduction with a bimetallic hydride such as lithiumaluminum hydride and chlorination of the resultingZ-hydroxymethylbenzofuran with a chlorinating agent such as phosphoruspentachloride, phosphorus trichloride or, preferably, thionyl chloride.

The compounds of the invention wherein n is 2 are preferably prepared bycondensing the acid halide of a thianaphthene or benzofuran-Z- or3-acetic acid with the appropriate 4-phenyl-4-piperidinol to give theacetamide, and this amide reduced with a reagent such as lithiumaluminum hydride. The requisite acetic acids are either described in theliterature or are prepared by reaction of a halomethylthianaphthene orbenzofuran with an alkali metal cyanide such as sodium cyanide, and thenhydrolyzing the resulting acetonitrile with a base such as aqueouspotassium hydroxide.

The compounds of the invention wherein n is 4 are preferably prepared byhomologating the corresponding propionic acid intermediates through theuse of the Arndt- Eistert reaction. The acid is converted to its acidhalide, condensed with diazomethane, and the resulting diazoketonetreated with a 4-phenyl-4-piperidinol in the presence of silver oxide togive an amide, which is reduced in the conventional manner to theproduct. Alternatively, the diazoketone is hydrolyzed with aqueoussilver oxide to the butyric acid, which is then converted via its acidchloride to the 4-phenylpiperidine amide, and the amide reduced to theproduct in the customary manner.

The various product compounds wherein R is methyl are generally preparedfrom the known carboxylic acids or halomethyl compounds possessing themethyl group. A further method for preparing 2- or 3-halomethylcompounds having a 2- or 3-methyl group involves reaction of achloromethyl compound with magnesium and carbon dioxide [1. Am. Chem.Soc. 74, 766 (1952)] to give the methyl carboxylic acid, and subsequentconversion by disclosed methods of the carboxy group to the halomethyland then to the higher alkanoic acids.

The compounds of the invention in which R is lower alkanoyl are preparedby acylating the corresponding hydroxy compound in the conventionalmanner with an anhydride or acyl halide such as acetic anhydride,propionyl chloride, butyryl chloride, or hexanoyl chloride.

Compounds of Formula IIb, which are 1,2,5,6-tetrahydropyridines, areprepared by dehydration of the corresponding 4-piperidinols withrefluxing concentrated hydrochloric acid.

Compounds in which Y is sulfone are prepared by oxidizing thecorresponding thianaphthene in which Y is sulfur with 30% hydrogenperoxide and glacial acetic acid.

The piperidinol compounds (R =H) of Formula I and the tetrahydropyridinecompounds of Formula IIb are tranquilizers. They have been found tocause a tranquilizing or sedative effect in rats when administered inoral doses of 200 mg./kg. They are formulated for use by combining themin amounts of 1-500 mg. with standard pharmaceutical excipients intosolid and liquid oral dosage forms and injectables by methods well knownto pharmaceutical chemists.

The ester compounds (R alkanoyl) of Formula I are analgesics. They havebeen found to produce analgesia in rats in oral doses of 10-25 rug/kg.They are formulated for use by combining them in amounts of 1250 mg.with standard pharmaceutical excipients into solid and liquid oraldosage forms and injectables by methods similarly well known topharmaceutical chemists.

Oral dosage forms may be in the form of tablets, capsules, troches, orlozenges. In a tablet, the active component is generally incorporatedinto a solid carrier. Among the acceptable solid carriers are lactose,sucrose, magnesium stearate, stearic acid, starch, terra alba, talc,calcium phosphate, gelatin, agar, pectin, and acacia. A time-delaymaterial such as glyceryl monostearate or glyceryl distearate, alone orwith a wax, may also be included.

A capsule may be prepared by placing the active component, either aloneor incorporated into a solid carrier, in a hard gelatin capsule. Aliquid formulation may consist of the active component suspended ordissolved in a liquid carrier such as peanut oil, olive oil, sesame oil,or water. The liquid formulation may be consumed orally as such,included in a soft gelatin capsule, or placed in an ampule. Aninjectable formulation may consist of a solution of the active componentin normal saline solution, water, or sugar solution, possibly withpreservatives such as Merthidate or parabens added.

Suppositories may also be prepared, containing 1-50 mg. of activecompound and such components as glycerin, glycerin monopalmitate,glyceryl monostearate, hydrogenated cocoanut oil fatty acids, andlecithin.

The following examples are intended to illustrate the preparation of thecompounds of the invention, but are not to be construed as limiting thescope thereof.

EXAMPLE 1 1- [3 5-chloro-2-thianaphthenyl) propyl] -4-phenyl-4-piperidinol To a stirred mixture of 5.38 g. of 56.1% NaH in mineral oil(0.125 mole of NaH) in 75 ml. of dimethyl sulfoxide is added dropwise20.1 g. (0.125 mole) of diethyl malonate in 20 ml. of dimethylsulfoxide. The mixture is stirred in a hot water bath for a half hour,cooled to room temperature, and a solution of 13.67 g. (0.063 mole) ofS-chloro-2-chloromethylthianaphthene in 50 ml. of dimethyl sulfoxideadded. The mixture is stirred on the steam bath for 1 hour, cooled, andpoured into water. The mixture is then extracted with ether, and theethereal extracts washed, dried, and evaporated. The residue isdissolved in acetonitrile, washed with petroleum ether, the petroleumether solution Washed with acetonitrile, and the combined acetonitrilesolutions evaporated. The residue is distilled, the distillate up to180/ 0.5 mm. being discarded. The product diethyl(5-chloro-2-thianaphthenylmethyl)- malonate distills at 180-20'2/ 0.5mm.

A mixture of 8.3 g. (0.0244 mole) of the above malonate, 9.5 g. of KOH,15 ml. of water, and 100 ml. of alcohol are refluxed With stirringovernight. The mixture is diluted with water and concentrated in vacuoto remove the alcohol. The residue is then diluted with water and ether,and the layers separated. The aqueous solution is washed with ether, theether washed with Water; the aqueous solution is acidified with HCl andextracted with ether. The ethereal extracts are dried and evaporated togive the (5-chloro-2-thianaphthenylmethyl)malonic acid, M.P. 194-196".

The above malonic acid (6.5 g., 0.0229 mole) is heated in an oil bath to240, and kept at 210-230 for 1 hour. The resulting3-(5-chloro-2-thianaphthenyl)propionic acid, when cooled, solidifies andmelts at 135145.

To a solution of this propionic acid in 25 ml. of acetone is added asolution of 4.1 g. (0.04 mole) of triethylamine in ml. of acetone. Thesolution is cooled to -10 and a solution of 4.35 g. (0.04 mole) of ethylchloroformate in 10 ml. of acetone is added dropwise. The resultingsolution is stirred in a salt-ice bath for 10 minutes and allowed towarm to room temperature, and a slurry of 9.2 g. (0.052 mole) of4-phenyl-4-piperidinol in 60 ml. of acetone is added. The resultingmixture is stirred and refluxed for 2 hours and poured into water andether. The layers are separated, the aqueous solution is washed withether, and the combined ether extracts are washed, dried, and evaporatedto give 1-[3-(5-chloro-2-thianaphthenyl)-propionyl]-4-phenyl-4-piperidinol, recrystallized from ethylacetate-hexane, M.P. 123-126.

To a stirred mixture of 4.5 g. of LiAlh in 600 ml. of dry ether is addeda solution of 9.1 g. (0.0227 mole) of the above amide in 100 ml. of drytetrahydrofuran and 300 ml. of dry ether. The resulting mixture isstirred and refluxed for 2 hours, and water and 10% NaOH are addeddropwise. The mixture is then filtered, the ethereal filtrate washed andextracted with dilute HCl and water, and the combined aqueous extractsmade basic with NaOH. Extraction with ether, and washing, drying, andevaporating the ether extracts gives the title product. The compound isdissolved in alcohol, ethereal HCl is added, and the hydrochloride saltis filtered off and recrystallized from alcohol-ether; M.P. 2l8220.

EXAMPLE 2 4-phenyl-1-[3-(3-thianaphthenyl)propyl]-4-piperidinol To amixture of 4.12 g. (0.02 mole) of 3-(3-thianaphthenyl)propionic acid in20 ml. of acetone and 4 m1. of water is added 3.6 g. (0.035 mole) oftriethylamine in 10 ml. of acetone. The solution is cooled to 10 and asolution of 3.8 g. (0.035 mole) of ethyl chloroformate in 10 ml. ofacetone is added dropwise. The resulting solution is stirred for 5minutes at 10, allowed to warm to room temperature, and 8.03 g. (0.0454mole) of 4- phenyl-4-piperidinol in 50 ml. of acetone added. Theresulting mixture is refluxed for 2 hours and allowed to stand for 2days. The resulting white precipitate of the hydrochloride of thestarting piperidinol is filtered off, the filtrate is evaporated invacuo and triturated with methylene chloride, and the mixture againfiltered. The filtrate is washed, dried, and evaporated and the residueof 4 phenyl 1 [3 (3 thianaphthenyl)propionyl] 4- piperidinolrecrystallized by dissolving in hot ethyl acetate and reprecipitatingwith hexane; M.P. 94-98".

To a stirred mixture of 2.0 g. of LiAlH in 200 ml. of dry ether is added5.0 g. (0.0137 mole) of the above amide in 400 ml. of dry ether. Theresulting mixture is stirred and refluxed for 3 hours and allowed tostand overnight at room temperature. The mixture is then refluxed for afurther 4 hours, water and 10% NaOH are added dropwise, and the mixtureis filtered. The filtrate is washed with water and extracted with diluteHCl, and the combined aqueous solutions basified with NaOH. Extractionwith ether-methylene chloride, and washing, drying, and evaporating theorganic extracts gives the title product, M.P. 107110. The basic productis then dissolved in Warm alcohol and filtered, and ethereal HCl addedto the filtrate. The resulting hydrochloride salt is recrystallized fromalcohol-ether and melts at 209211.

EXAMPLE 3 4-phenyl-1-[3-(2-thianaphthenyl) propyl] -4-piperidinol To 250ml. of absolute alcohol is added 4.6 g. (0.2 mole) of sodium cut intopieces. This mixture is stirred for one-half hour and 35.3 g. (0.22mole) of diethyl malonate is then added. The mixture is then stirred andrefluxed for 2 hours and a solution of 1.82 g. (0.1 mole) of2-chloromethylthianaphthene in ml. of dry ether is added. The ether isboiled off and the remaining solution is refluxed overnight. Thereaction mixture is poured into ice water and extracted with ether. Theether extracts are washed, dried, and evaporated, andwthe residue isdistilled. The forerun distilling up to /0.5 mm. is discarded. Thefraction boiling at 170-176/ 0.5 mm. is collected and is diethyl(Z-thianaphthenylmethyl)malonate.

A solution of 11.0 g. (0.0359 mole) of the above malonate and 15 g. ofKOH in 500 ml. of ethanol and 50 ml. of water is refluxed with stirringfor 4 hours and then evaporated in vacuo. The residue is dissolved inwater, washed with ether, the ether washings being then washed withwater, and the combined aqueous solutions acidified with HCl. The acidicsolution is extracted with ether and the ether extracts washed, dried,and evaporated to give (2 thianaphthenylmethyl)malonic acid, M.P.181-183.

The above malonic acid (7.6 g., 0.031 mole) is heated in an oil bath at230-250 for one-half hour and the melt is cooled to give3-(Z-thianaphthenyl)propionic acid.

To a solution of this acid in 34 ml. of acetone is added a solution of5.55 g. (0.0542 mole) of triethylamine in 13.5 ml. of acetone. Theresulting solution is stirred in a salt-ice bath at 10-0 while asolution of 5.89 g. (0.0542 mole) of ethyl chloroformate in 13.5 ml. ofacetone is added dropwise. The mixture is then stirred in ice for 10minutes, allowed to warm to room temperature, and an additional 80 ml.of acetone added, followed by 12.45 g. (0.0704 mole) of4-phenyl-4-piperidinol. The reaction mixture is refluxed for 2 hours,allowed to stand overnight at room temperature, and then poured intoether-water. The layers are separated, the aqueous layer washed withether, and the combined ether extracts washed successively with water,dilute HCl, water, dilute NaOH, and water. When the ether solution isdried and evaporated, 4-phenyl-l-[3-(2-thianaphthenyl)propionyl]-4-piperidinol is obtained.

To a stirred mixture of 6.0 g. of LiAlH in 800 ml. of dry ether is addeda solution of 11.31 g. (0.031 mole) of the above amide in 80 ml. of drytetrahydrofuran. The resulting mixture is refluxed for 3 hours andallowed to stand overnight at room temperature, and 25 ml. of water and6 ml. of 10% NaOH added dropwise. The mixture is then stirred forone-half hour and filtered, and the filtrate washed with water andextracted with dilute HCl. The acidic extracts are basified with 40%NaOH and extracted with ether. The ether extracts are washed, dried, andevaporated to give the title product. This product is dissolved inalcohol and ethereal HCl added to give the hydrochloride salt of theproduct. Recrystallization is achieved using alcohol-ether; M.P.209-211".

EXAMLE 4 l- [3-(2-benzofu ranyl) propyl]-4-phenyl-4-piperidinol To astirred mixture of 19.2 g. of 56.1% NaH in mineral oil (10.7 g., 0.444mole of NaH) in 265 ml. of dimethyl sulfoxide is added dropwise asolution of 7.15 g. (0.444 mole) of diethyl malonate in 70 ml. ofdimethyl sulfoxide. The mixture is then stirred in a hot water bath for1 hour and cooled to room temperature. A solution of 37.3 g. (0.224mole) of 2-chlorornethylbenzofuran in 150 ml. of dimethyl sulfoxide isadded dropwise, the mixture is refluxed with stirring for 1 hour, and isthen poured into water-ether. The layers are separated, the aqueoussolution is washed with ether, and the combined ether extracts arewashed, dried and evaporated in vacuo. The residue is dissolved inacetonitrile and washed with petroleum ether, the petroleum ethersolution extracted with acetronitrile, and the combined acetonitrileextracts evaporated in vacuo. The residue is distilled through asilvered column and the material distilling at 143/0.5 mm. collected.This compound is diethyl (2-benzofuranylmethyl)malonate.

A mixture of 31.9 g. of KOH in 50 ml. of water and 31.9 g. (0.11 mole)of this malonate ester in 500 ml. of alcohol is stirred and refluxed for3 hours and then evaporated in vacuo. The residue is dissolved in waterand the aqueous solution washed with ether and acidified withconcentrated HCl. The acid solution is extracted with ether and theethereal extracts washed, dried, and evaporated to give(Z-benzofuranylmethyl)malonic acid, M.P. 171-172".

This acid (12.5 g., 0.0535 mole) is heated in an oil bath to 260 andallowed to cool, the product being 3-(2-benzofuranyl)propionic acid,M.P. 109112. This compound is dissolved in 40 ml. of acetone and 6.7 g.(0.0653 mole) of triethylamine in 16 ml. of acetone is added. Thesolution is cooled in salt-ice to 10 and a solution of 7.1 g. (0.0653mole) of ethyl chloroformate in 16 ml. of acetone added dropwise. Theresulting mixture is stirred with cooling for minutes and allowed towarm to room temperature, after which a slurry of 15.0 g. (0.0849 mole)of 4-phenyl-4-piperidinol in 100 ml. of acetone is added. The mixture isstirred at reflux for 2 hours, allowed to stand overnight at roomtemperature, refluxed for an additional hour and a half, and then pouredinto Water-ether. The layers are separated, the aqueous layer extractedwith ether, and the combined ethereal solutions washed, dried, andevaporated in vacuo to give as a gum,4-phenyl-1-[3-(2-benzofuranyl)propionyl]-4-piperidinol, which when etheris added solidifies; M.P. 103-105.

To a stirred mixture of 7.5 g. of LiAlH in 300 ml. of dry ether isslowly added a solution of 0.0374 mole of the above amide in ml. of drytetrahydrofuran and 600 ml. of dry ether. The mixture is stirred andrefluxed for 3 hours, allowed to stand at room temperature overnight,and then 30 ml. of water and 7.5 ml. of 10% NaOH cautiously added. Themixture is filtered, the filter cake being washed well withtetrahydrofuran, and the combined organic extracts extracted with diluteHCl. The acidic extracts are made basic with 40% NaOH, extracted withether, and the ethereal extracts washed, dried, and evaporated in vacuoto give the title product. A hydrochloride salt is formed by adding toan alcoholic solution of the free base ethereal HCl and recrystallizingfrom alcohol-ether; M.P. 148151.

EXAMPLE 5 1- [3 3-benzofuranyl pro pyl-4-phenyl-4-pi peridinol Theprocedures of Examples 1, 3 or 4 are followed. 3-chloromethylbenzofuranis condensed with sodio diethyl malonate to give diethyl(3-benzofuranylmethyl)malomate. The malonate is hydrolyzed to the diacidwith aqueous KOH, monodecarboxylated by heating, ethyl chloroformate isadded to the triethylamine salt of the resulting propionic acid, and4-phenyl-4-piperidinol added to the resulting ester anhydride to give apropionamide. The amide is reduced to the product with LiA1H EXAMPLE 64-p-chlorophenyl-1-[3-(3-thianaphthenyl)propyl]-4- piperidinol Theprocedure of Example 2 is followed. 3-(3-thianaphthenyl)propionic acidis converted to its triethylamine salt and then the salt allowed toreact with ethyl chloroformate. The resulting ester anhydride iscondensed with 4-p-chlorophenyl-4-piperidinol to give an amide, which isreduced with LiAlH to give the product.

Use of 4-p-tolyl-4-piperidinol or4-p-trifluoromethylphenyl-4-piperidinol in the above procedure insteadof 4-p-chlorophenyl-4-piperidinol results in the formation of 1 [3 (3thianaphthenyl)pr0pyl] 4 p tolyl 4- piperidinol or 1 [3 (3thianaphthenyl)propylj 4 ptrifluoromethylphenyl-4-piperidinol,respectively.

Use of 4-m-bromophenyl-4-piperidinol or 4- o-tolyl-4- piperidinol in theabove procedure instead of 4-p-chlorophenyl-4-piperidinol results in theformation of 4-mbromophenyl 1 [3 (3 thianaphthenyl)propyl] 4-piperidinol or 1 [3 (3 thianaphthenyl)propyl] 4 otolyl-4-piperidinol,respectively.

Use of fluoro or methoxy substituted phenylpiperidinols results in theformation of the corresponding fluoro or methoxy substituted products.

EXAMPLE 7 4-p-chlor0phenyl-1- 3- (6-fluoro-3-thianaphthenylpropyl]-4-piperidinol The procedures of Examples 1, 3, or 4 arefollowed. 6-fluoro-3-chlorornethylthianaphthene is condensed with sodiodiethyl malonate to give diethyl(6-fluoro-3-thianaphthenylmethyl)malonate. The malonate is hydrolyzed tothe diacid with aqueous KOH, the diacid monodecarboxylated by heating,ethyl chloroformate is added to the triethylamine salt of the resultingpropionic acid, and 4-p-chlorophenyl-4-piperidinol added to theresulting estcr anhydride to give a propionamide. Reduction of the amidewith LiAlH, gives the product.

Use of 6-chloro-3-chloromethylthianaphthene as starting material insteadof 6 fluoro 3 chloromethylthianaphthene results in the formation of4-p-chlorophenyl-l- [3-(6-chloro-3-thianaphthenyl) propyl]-4-piperidinol.

Use of 6 trifluoromethyl-3-chloromethylthianaphthene,

-methyl-3-chloromethylthianaphthene,

5-butyl-2-chloromethylthianaphthene,

6-bromo-3-chloromethylbenzofuran,

6-methoxy-2-chloromethylthianaphthene, or

6-butoxy-2-chloromethylbenzofuran as starting material instead of6-fluoro-3-ch1oromethylthianaphthene results in the formation of4-p-chlorophenyll 3- fi-trifluoromethyl-3-thianaphthenyl pro pyl}-4-piperidinol,

4-p-chlorophenyl-1- [3- 5 -methyl-3-thianaphthenyl) propyl]-4-piperidinol,

1- [3- 5 -butyl-2-thianaphthenyl propyl]-4-p-chlorophenyl-4-piperidinol,

l- 3- 6-bromo-3-benzofuranyl pro pyl] -4-p-chlorophenyl-4-piperidinol,

4-p-chlorophenyl-1-[3-(6-methoxy-2-thianaphthenyl)- propyl]-4-piperidinol, or

1- 3- 6-butoxy-2-benzofuranyl pro pyl -4-p-chlorophenyl-4-piperidinol,

respectively.

Use of 4-p-fluorophenyl-4-piperidinol in the above procedure instead of4-p-chlorophenyl-4-piperidinol results in the formation of4-p-fluorophenyl-l-[3-(6-fluoro- 3-thianaphthenyl) pro pyl]-4-piperidinol.

EXAMPLE 8 4-phenyl-1- [2- 3-thianaphthenyl) ethyl] -4-piperidinol Amixture of 15.0 g. (0.0824 mole) of thianaphthene- 3-acetic acid [1. Am.Chem. Soc. 70, 3768 (1948)] and 30 ml. of SOCl is allowed to standovernight at room temperature. The solution is diluted with benzene andevaporated in vacuo, and the procedure repeated. The residue isdissolved in ca. 500ml. of dry toluene and 29.3 g. (0.165 mole) of4-phenyl-4-piper.idinol added. The mixture is stirred and refluxed for 2hours, allowed to stand overnight at room temperature, and filtered. Thefiltrate is washed successively with dilute HCl, water, NaOH, and water,dried and evaporated in vacuo to give 4-phenyl-1- [2-(3-thianaphthenyl)acetyl] -4-piperidinol.

To a stirred mixture of 14.5 g. of LiAlH in 1 liter of dry ether isadded slowly a solution of 26.3 g. (0.0824 mole) of the above amide in100 ml. of dry tetrahydrofuran and 300 ml. of dry ether. The resultingmixture is refluxed for 2 hours, allowed to stand overnight at roomtemperature, and refluxed again for 2 hours. A total of ca. 60 ml. ofwater and ml. of 10% NaOH is then added dropwise, the mixture stirredfor one and one-half hours, and then filtered. The filtrate is washedwith Water and extracted with dilute HCl. The acidic and ethereal layersare filtered, and any solid obtained is dissolved in hot alcohol towhich NaOH is added and this mixture then combined with the acidicextracts after they have been basified with NaOH. The total mixture isextracted with ether and the ethereal extracts washed, dried, andevaporated to give the title product. When the product is dissolved inalcohol and ethereal HCl added, and then ether, a hydrochloride salt,which is then recrystallized from alcohol-ether is obtained; M.P.224226.

EXAMPLE 9 4-phenyl-1- [4- (3 -thianaphthenyl butyl] -4-piperidinol To astirred mixture of 78 g. of 57% NaH in mineral oil (44.5 g., 1.856 molesof NaH) in 1150 ml. of dry dimethyl sulfoxide, maintained in ice at25-30", is added dropwise a solution of 297 g. (1.856 moles) of diethylmalonate in 230 m1. of dimethyl sulfoxide. The resulting solution isstirred in a hot water bath at 5060 for an hour and then cooled to roomtemperature, after which a solution of 170.0 g. (0.93 mole) of3-chloromethylthianaphthene in 150 ml. of dry dimethyl sulfoxide isadded dropwise. The resulting solution is heated on the steam bath foran hour, cooled, and poured into ice water.

The mixture is extracted with ether, and the ethereal extracts washed,dried, and evaporated. The residue is distilled under vacuum, thefractions distilling at 123- 232/0.4 mm. being diethyl(3-thianaphthenylmethyl)- malonate.

A solution of 200 g. of KOH, 200 g. of water, and 131.2 g. (0.428 mole)of the above malonate in 2000 ml. of alcohol is stirred and refluxed for4 hours and evaporated in vacuo. The residue is dissolved in water andwashed with ether. The aqueous solution is cooled, acidified withconcentrated HCl, and extracted with ether. The ethereal extracts arewashed, dried, and evaporated in vacuo, and the residue triturated withhexane to give (3- thianaphthenyl)malonic acid, M.P. 170171 dec.

The above malonic acid (17.5 g., 0.07 mole) is heated in an oil bath toca. 250 and then at 230 for 1 hour. The melt is allowed to coolfollowing the decarboxylation and 40 ml. of SOCl added. After beingallowed to stand overnight at room temperature, the mixture is refluxedon the steam bath for one-half hour and then evaporated in vacuo,benzene being added .to the residue to eliminate traces of SOCI Theresidue is the acid chloride of 3-(3- thianaphthenyl)-propionic acid.

A solution of diazomethane .is prepared as follows: To an unscratched 2liter Erlenmeyer flask on a magnetic stirrer with a Teflon bar immersedin a salt-ice bath is added 75 ml. of 50% KOH and 200 ml. of ether. Whenthe internal temperature of the mixture is below 0, 29.4 g. (0.2 mole)of N-methyl-N-nitro-N-nitrosoguanidine is added in small portions suchthat the internal temperature remains below 5. The cold mixture isstirred in a salt-ice bath for 5 mintues and allowed to settle, and theether solution decanted into an unscratched 2 l. Erlenmeyer flaskcontaining KOH pellets and cooled in ice. The reaction mixture isextracted with 6-100 m1. portions of cold ether, the ether extractsdried in an ice bath with KOH pellets for one-half hour, and thenfiltered into an unscratched 2 liter filter flask in an ice bath,equipped With a magnetic stirrer. The solution is stirred in ice whilea. solution of 15.7 g. (0.07 mole) of the above acid chloride in a smallamount of methylene chloride is added dropwise, nitrogen being evolved.The resulting solution is allowed to stand overnight, the ice bath beingallowed to warm to room temperature and the solution is evaporated invacuo using a hot water bath, a hood, and a safety shield, to leave asthe residue 1-diazo-4-(3-thianaphthenyl) -2-butanone.

To a mixture of 14.0 g. (0.079 mole) of 4-phenyl-4- piperidinol in ca.300 ml. of dioxane which has been heated to achieve partial solution andthen cooled to room temperature, is added a solution of 16.1 g. (0.07mole) of the above diazoketone in ml. of dioxane, followed by 2.0 g. ofAg O. The mixture is stirred in a water bath at 60-70 for one-half hour,nitrogen being evolved. An additional 0.5 g. of Ag O is added, followedby heating at 60-70 for one-half hour and a final 0.5 g. portion of Ag Oadded and heated. The mixture is allowed to stand overnight at roomtemperature and then filtered through Super-Gel, and the filtrateevaporated in vacuo. The residue is dissolved in methylene chloride, andwashed with acid, base, and water, and evaporated in vacuo to give4-phenyl-1-[4-(3-thianaphthenyl)-butyryl] -4-pip eridinol.

To a stirred mixture of 5.7 g. (0.15 mole) of LiAlH in 1000 ml. of dryether is slowly added a solution of ca. 26 g. (0.07 mole) of the aboveamide in ca. 200 ml. of dry tetrahydrofuran. The resulting mixture isstirred and refluxed for 4 hours and then a total of ca. 25 ml. of waterand6 ml. of 10% NaOH added dropwise. The mixture is stirred for one-halfhour and filtered. The filtrate is dried, charcoaled, filtered throughSuper- Cel, and evaporated in vacuo to give the title product,recrystallized from toluene; M.P. 126131. When the free base isdissolved in alcohol and ethereal HCl added, a hydrochloride salt isformed; recrystallized from alcohol-ether; M.P. 183-186".

1 1 EXAMPLE 1o 1- 3- 2-methyl-3-thianaphthenyl propyl] -4-phenyl-4-piperidino1 2-methyl-3-thianaphthenecarboxylic acid is reduced withLiAlH, according to standard procedure to give3-hydroxymethyl-2-methylthianaphthene. The hydroxymethyl group isconverted to chloromethyl with SOCl as described in Procedure 1 and theproduct condensed with diethyl malonate as in Example 1. By followingthe rest of the steps of Example 1, including hydrolysis,decarboxylation, formation of the ester anhydride and then the amide,and finally reduction with LiAlH the title product is obtained.

EXAMPLE 1 1 When 5-chloro-3-methylbenzofuran-2-acetic acid and5-methoxy-Z-methylbenzofuran-3-acetic acid are substituted for thethianaphthene-3-acetic acid in the procedure of Example 8, and the acidchloride formation, amide formation, and reduction carried out asdescribed therein, 1 [2 (5 chloro 3 methyl 2 benzofuranyl)ethyl]4-phenyl-4-piperidinol and 1-[2-(5-methoxy-2-methyl-3- benzofuranylethyl] -4-phenyl-4-piperidinol, respectively, are obtained.

When 6 methoxy-3-benzofuranbutyric acid and 5-methoxy-3-thianaphthenebutyric acid are substituted for thethianaphthene-B-acetic in the procedure of Example 8, and the acidchloride formation, amide formation, and reduction carried out asdescribed therein, 1-[4-(6- methoxy-3-benzofuranyl)butyl]-4 phenyl 4piperidinol and 1-[4-(5-methoxy-3-thianaphtheny1)butyl] 4 phenyl-4-piperidinol, respectively, are obtained.

EXAMPLE 12 A tablet may have the following composition:

4-phenyl-1-[3-(3-thianaphthenyl)propyl] 4 piperidinol hydrochloride 1OMagnesium stearate 2.5 Starch 15 Terra alba 150 Granulate with syrup or5% gelatin solution terra alba q.s. ad 300 An injectable solution mayhave the following composition per cc.:

4-phenyl-1-[3-(Z-thianaphthenyDpropyl] 4 piperidinol hydrochloride mg 5Sodium biphosphate mg 5 Sodium tartrate mg 12 Sodium saccharin mg 0.9Benzyl alcohol percent 0.75 Water q.s. ad cc 1 EXAMPLE 134-phenyll-[3-(3-thianaphthenyl) propyl] 4-piperidinol O-acetate Asolution of 4.2 g. (0.012 mole) of 4-phenyl-1-[3-(3-thianaphthenyl)propyl]-4-piperidinol and 2 or 3 drops of cone. H 50 in100 ml. of acetic anhydride is stirred on the steam bath for 3 hours andevaporated in vacuo. The residue is warmed and stirred with 5% Na COthen cooled, and methylene chloride added. The layers are separated andthe aqueous layer Washed with methylene chloride. The organic extractsare washed, dried, and evaporated in vacuo to give the title product.This free base is dissolved in alcohol, ethereal hydrogen chlorideadded, and the ether is added. Filtration gives the hydrochloride saltof the title product, which is triturated with ethyl acetate andrecrystallized from isopropanol-ether; M.P. 173-175".

12 EXAMPLE 14 4-phenyl-1-[3- (B-thianaphthenyl)propyl] -4-piperidinolO-propionate A 7.5 g. (0.0193 mole) sample of 4-phenyl-l-[3-(3-thianaphthenyl)propyl] 4 piperidinol hydrochloride is converted to thefree base and dissolved in 250 ml. of dry benzene. A solution of 1.8 g.(0.0193 mole) of propionyl chloride in 50 ml. of dry benzene is added,and the cloudy solution is stirred and refluxed for 1 hour and allowedto stand at room temperature overnight. The mixture is filtered and thefiltrate evaporated in vacuo to give the title product. The base isdissolved in alcohol, ethereal hydrogen chloride added, and the mixturethen diluted with ether. The hydrochloride salt of the title product isfiltered off and recrystallized from alcoholether; M.P. 177-179.

EXAMPLE 15 1,2,5,6-tetrahydro-4-phenyl- 1- 3- 3-thianaphthenyl) propyl]pyridine A mixture of 10.0 g. (0.0258 mole) of 4-phenyl-l-[3-(3-thianaphthenyl propyl] -4-piperidinol hydrochloride and ml. of 12N HCl is stirred and refluxed for 3 hours. The solution is concentratedin vacuo, the residue is dissolved in methanol, benzene is added, andthe mixture is evaporated to dryness. Recrystallization of the residuefrom ethanol-ether gives the hydrochloride of the title product, M.P.197-200. The free base is obtained in the usual manner.

When the following piperidinols are dehydrated according to the aboveprocedure, the corresponding listed tetrahydropyridines are obtained.

Piperidinol:

l-[3-(5-chloro-2-thianaphthenyl propyl]-4-pheny1- 4-piperidinol4-phenyl-1- [3-(2-thianaphthenyl) propyl] -4-piperidinol 1- [3(2-benzofuranyl propyl] -4-phenyl-4-piperidinol4-phenyl-1-[2-(3-thianaphthenyl ethyl] -4-piperidinol 4-phenyl- 1- [4-(3-thianaphthenyl) butyl] -4-piperidinol Tetrahydropyridine:1-[3-(5-chloro-Z-thianaphthenyl)propyl1-1,2,5,6-

tetrahydro-4-phenylpyridinel,2,5,6-tetrahydro-4-phenyl-1-[3-(2-thianaphthenyl) propylJpyridine 1-3- (2-benzofuranyl pro pyl] 1 ,2,5 ,6-tetrahydro-4- phenylpyridinel,2,5,6-tetrahydro-4-phenyl-1-[2-(3-thianaphthenyl) ethylJpyridine1,2,5,6-tetrahydro-4-phenyl-1-[4-(3-thianaphthenyl) butyl] pyridine'EXAMPLE 16 1-[3-( 1,1-dioxo-3-thianaphthenyl propyl]-4-phenyl-4-piperidinol A solution of 4.64 g. (0.012 mole) of 4-phenyl-1-[3-(3-thianaphthenyl)propyl]-4 piperidinol hydrochloride, 40 ml. of glacialacetic acid, and 12 ml. of 30% H 0 is heated at 60 for 1 hour. Themixture is stirred and refluxed for 15 minutes then diluted with icewater, made alkaline with NaOH, and extracted with methylene chloride.The organic extracts are washed, dried, and concentrated to give thetitle product. Addition of hydrogen chloride to an isopropanol solutionof the product, followed by ether gives the hydrochloride salt; M.P.228.5-230.

When the following thianaphthene compounds are oxidized according to theabove procedure, the corresponding listed sulfones are obtained.

Thianaphthene:

1-[3-(5-chloro-2-thianaphthenyl propyl]-4-pheny1-4- piperidinol4-phenyl-1- [3 Z-thianaphthenyl) propyl] -4-piperidinol 1 3 4-phenyl-1-[2- 3 -thianaphthenyl) ethyl] -4-piperidinol 4-phenyl- 1- [4-(3-thianaphthenyl) butyl] -4-piperidinol Sulfone:

1-[3-(S-chloro-1,1-dioxo-2-thianaphthenyl)propyl]-4-phenyl-4-piperidinol I1-[3-(1,1-dioxo-2-thianaphthenyl)propyl]4-phenyl-4- piperidinol 1- [2-(1, 1-dioxo-3-thianaphthenyl ethyl] -4-phenyl-4- piperidinol 1- [4- 1,l-dioxo-3 -thiar1aphthenyl) butyl] -4-phenyl'4 piperidinol PROCEDURE 15-chloro-2-chloromethylthianaphthene Dry ether (50 ml.) is added slowlyto a cooled; solution of 7.925 g. (0.124 mole) of butyl lithium in 80ml. of hexane under nitrogen. The cooled solution is stirred, a solutionof 16.8 g. (0.1 mole) of 5-chlorothianaphthene in 50 ml. of dry ether isadded slowly, and the resulting solution is stirred in ice for 2 hours.A 9.5 g. (0.32 mole) sample of paraformaldehyde (dried by heating on thesteam bath for 2 hours in vacuo) is placed in an oil bath at about 190,and the formaldehyde is swept into the reaction mixture with nitrogen.After addition is complete (ca. 1 hour), the mixture is stirred andrefluxed for 2-3 hours, and then allowed to stand overnight. The mixtureis diluted with 7.5 ml. of alcohol to destroy the remaining butyllithium and then with ca. 200 ml. of aqueous salt solution. The layersare separated, the aqueous layer is washed with ether, and the combinedetheral extracts are washed, dried, and evaporated in vacuo to give asolid. Trituration with petroleum ether and recrystallization fromtoluene gives 5-chloro-2-hydroxymethylthianaphthene, M.P. 122124.5.

To a stirred solution of 13.0 g. (0.0655 mole) of this compound in 100ml. of chloroform is added dropwise 12.0 ml. of SOCI The resultingmixture is stirred and refluxed for a half hour and then evaporated invacuo. The residue is dissolved in benzene and again evaporated to givethe title compound.

5-chlorothianaphthene, as well as the 5, 6, and 7- methylthianaphthenes,is described in Chemical Abstracts 47, 12346 gh.

We claim:

1. A member selected from the group consisting of compounds of theformula R1 (OH... O Q 6 Y R and the pharmaceutically acceptable acidaddition salts thereof, wherein:

R is at the or 6-position and is hydrogen, chloro, bromo, fluoro,trifluoromethyl, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4carbon atoms;

R is hydrogen, chloro, bromo, methyl, trifluoromethyl, fluoro, ormethoxy;

R is hydrogen or methyl;

R is hydrogen;

Y is oxygen, sulfur, or sulfone; and

n is a positive integer from 2 to 4.

2. A compound as claimed in claim 1, where R is hydrogen.

3. A composition as claimed in claim 2, where n is 3.

4. A composition as claimed in claim 3, where Y is sulfur.

5. A compound as claimed in claim 4, where R is hydrogen, chloro, orfluoro; R is at the p-position and is hydrogen, chloro, or fluoro; and Ris hydrogen.

6. A compound as claimed in claim 5, where R and R are both hydrogen,being the compound 4-phenyl-l-[3-(3-thianaphthenyl)propyl]-4-piperidinol or its hydrochloride salt.

7. A compound as claimed in claim 5, where R and R are both hydrogen,being the compound 4-phcnyl-1-[3-(Z-thianaphthenyl)propyl]-4-piperidinol or its hydrochloride salt.

8. A compound as claimed in claim 5, where R is 5- chloro and R ishydrogen, being the compound l-[3-(5- chloro-2-thianaphthenyl propyl]-4-phenyl-4-piperidinol or its hydrochloride salt.

9. A compound as claimed in claim 5, where R is hydrogen and R ischloro, being the compound 4-p-chlorophenyl- 1- 3- (3-thianaphthenylpropyl] -4-piperidinol or its hydrochloride salt.

10. A compound as claimed in claim 2, where R is hydrogen, R isp-methyl, n is 3, and Y is sulfur, being the compound 1-[3 (3thianaphthenyl)propyl]-4-p-tolyl-4- piperidinol or its hydrochloridesalt.

11. A compound as claimed in claim 2, where R is hydrogen, R isp-trifluoromethyl, n is 3, and Y is sulfur, being the compound1-[3-(3-thianaphthenyl)propyl]-4-ptrifluoromethylphenyl-4-piperidino1 orits hydrochloride salt.

12. A compound as claimed in claim 5, where R and R are both chloro,being the compound 4-p-chlorophenyl-1-[3-(6-chloro-3-thianaphthenyl)propyl]-4-piperidinol or itshydrochloride salt.

13. A compound as claimed in claim 5, where R is 6- fluoro and R ischloro, being the compound4-p-chlorophenyl-l-[3-(6-fiuoro-3-thianaphthenyl)propyl] 4-piperidinolor its hydrochloride salt.

14. A compound as claimed in claim 2, Where R and R are hydrogen, n is2, and Y is sulfur, being the compound4-phenyl-l-[2-(3-thianaphthenyl)ethyl] 4 piperidinol or itshydrochloride salt.

15. A compound as claimed in claim 2, where R and R are hydrogen, n is4, and Y is sulfur, being the compound 4-phenyl-1-[4-(3-thianaphthenyl)butyl] 4 piperidinol or its hydrochloride salt.

16. A compound as claimed in claim 1, where Y is oxygen.

17. A compound as claimed in claim 16, where R, R and R are eachhydrogen and n is 3, being the compound l-[3-(3-benzofuranyl) propyl]-4-phenyl 4 piperidinol or its hydrochloride salt.

18. A compound as claimed in claim 16, where R, R and R are eachhydrogen and n is 3, being the compound1-[3-(2-benzofuranyl)propyl]-4-phenyl 4 piperidinol or its hydrochloridesalt.

References Cited UNITED STATES PATENTS 3,070,606 12/1962 Anderson260293.45

FOREIGN PATENTS 632,437 12/1961 Canada.

OTHER REFERENCES I. Neuropharmacol, 1962, vol. 1, pp. -48; Janssen.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US.Cl. X.R.

